Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
  • C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/10—Antimycotics
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
  • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
  • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
  • C07C211/30—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the six-membered aromatic ring being part of a condensed ring system formed by two rings

Definitions

• the present invention belongs to the field of pharmaceutical chemistry and relates to a novel process for preparing terbinafine and the pharmaceutically acceptable salts thereof.
• Terbinafine or (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-1-naphthalenemethanamine, is a known medicament with antifungal activity for topical use and has been first disclosed in EP 024587.
• the (E) stereoisomer of said compound is biologically active.
• various alternative processes for its production more advantageous than those disclosed in EP 024587, have been developed, particularly those disclosed in EP 421302, WO 02/02503 and EP 1236709.
• EP 421302 and WO 02/02503 disclose processes in which the last synthetic step comprises the reaction of N-(3-chloro-2-propenyl)-N-methyl-1-naphthalenemethanamine with tert-butylacetylene, in the presence of an organic amine and catalytic amounts of palladium salts and copper(I) iodide.
• Palladium compounds conventionally used for the coupling reaction known as “palladium catalyst-cross coupling reaction” are used as palladium catalysts.
• Examples of the palladium compounds reported in EP 421302 and WO 02/02503 comprise palladium-tertiary phosphine complexes, combinations of a palladium salt with a tertiary phosphine and a combination of a palladium complex with a tertiary phosphine.
• the processes described in said documents afford terbinafine in good yields but they have some remarkable drawbacks: for instance, the final product is contaminated by palladium and decomposition products of the palladium-phosphorous complexes, which have to be removed with cumbersome, expensive purification processes, for example by liquid column chromatography.
• EP 1236709 has overcome the drawbacks connected with the use of palladium catalysts, by reacting N-(3-chloro-2-propenyl) -N-methyl-1-naphthalenemethanamine with tert-butylacetylene in alkali medium in the presence of copper(I) salts only.
• This process affords terbinafine free from catalyst contaminations in good yield, but it requires long reaction times, which do not suitably meet the requirements for the industrial production on a large scale.
• the inventors of the present invention have surprisingly found a novel process for the preparation of terbinafine, which can be carried out in comparatively short reaction times and affords a product free from catalyst contaminations and other reaction by-products, and moreover in significantly quantitative yield and improved stereoisomeric (E/Z) ratio.
• the present invention relates to a process for preparing terbinafine, or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula (II), or a salt thereof,
• X is a leaving group, with tert-butylacetylene, in the presence of a platinum catalyst.
• the leaving group X is a conventional leaving group, for example a halogen atom, in particular chlorine, bromine or iodine, a perfluoroalkylsulfonic group, in particular perfluorooctylsulfonic or perfluorobutylsulfonic, or an an esterified hydroxy group, e.g. a —O-mesyl or —O-tosyl group.
• a salt of a compound of formula (II) is a salt with an organic or inorganic acid and is a further object of the invention.
• Examples of salts of a compound of formula (II) are hydrochloride, hydrobromide, sulfate, fumarate, formate, acetate, propionate, tartrate, citrate, oxalate, malonate, maleate, methanesulfonate, paratoluenesulfonate or benzoate or a derivative thereof wherein the phenyl ring is optionally substituted with one or two groups independently selected from chlorine, bromine, iodine, hydroxy, nitro, C 1 -C 6 alkyl and C 1 -C 6 alkoxy.
• a preferred salt is N-(3-chloro-2-propenyl)-N-methyl-1-naphthalenemethanamine oxalate.
• reaction between a compound of formula (II), or a salt thereof, and tert-butylacetylene is carried out in an organic solvent, in the presence of a platinum catalyst and a basic agent.
• the same reaction can be carried out in the presence of additional amounts of a copper compound.
• the platinum catalyst is platinum metal or a derivative thereof, for example platinum acetylacetonate, platinum bis(benzonitrile)dichloride, platinum oxide, a platinum halide, such as platinum chloride, bromide and iodide, or platinum acetate, in particular, platinum chloride or platinum metal, the latter preferably on an inert support, such as carbon, silica or alumina, preferably carbon.
• platinum metal on a carbon support e.g. charcoal, with platinum content from about 1% to about 10%, preferably from about 5% to about 10%.
• a copper compound is for example copper (I) chloride, copper (I) bromide, copper (I) iodide, copper acetate or copper (I) oxide, preferably copper (I) iodide.
• the organic solvent can be an organic protic solvent, such as methanol or ethanol; a halogenated hydrocarbon, such as chloroform or dichloromethane; an aromatic hydrocarbon, such as benzene or toluene; an ether, such as diethyl ether, tetrahydrofuran or dioxane; or an organic aprotic solvent, such as dimethylformamide, dimethyl sulfoxide or acetonitrile.
• an organic protic solvent such as methanol or ethanol
• a halogenated hydrocarbon such as chloroform or dichloromethane
• an aromatic hydrocarbon such as benzene or toluene
• an ether such as diethyl ether, tetrahydrofuran or dioxane
• an organic aprotic solvent such as dimethylformamide, dimethyl sulfoxide or acetonitrile.
• the basic agent can be an organic or inorganic base.
• organic base are trimethylamine, triethylamine, pyridine, piperidine, butylamine, N,N-dimethylformamide and 4-dimethylaminopyridine, preferably piperidine or butylamine.
• inorganic base are sodium or potassium hydroxide, bicarbonate and carbonate.
• the organic base itself for example piperidine, pyridine or triethylamine, can act as the organic solvent when used in a large excess, typically in amounts approx. from 3 to 20 equivalents per equivalent of a compound of formula (II), or a salt thereof.
• the coupling reaction between tert-butylacetylene and a compound of formula (II), or a salt thereof can be carried out using stoichiometric amounts of the two reagents, or a tert-butylacetylene excess, for example approximately from 1 to 2, preferably approximately 1.3-1.6, equivalents of tert-butylacetylene per equivalent of a compound of formula (II), or a salt thereof.
• the amount of platinum catalyst is preferably approximately equal to or lower than 10% molar with respect to a compound of formula (II), or a salt thereof, typically lower than approximately 3%-10% molar.
• the amount of a copper compound is preferably a catalytic amount and its molar amount is usually twice the molar amount of platinum catalyst.
• the reaction is typically carried out adding tert-butylacetylene to a dispersion of compound of formula (II), or a salt thereof, platinum catalyst and basic agent in the organic solvent, optionally also adding a copper compound as defined above.
• the reaction is carried out with stirring and preferably under inert atmosphere, for example under nitrogen atmosphere.
• tert-butylacetylene is added to a dispersion of compound of formula (II), or a salt thereof, platinum catalyst and optionally copper compound in piperidine.
• the reaction temperature can range from about 0° C. to about 80° C., preferably from about 20° C. about 90° C., more preferably from about 30° C. to about 80° C.
• Reaction times approximately range about from 3 to 10 hours, preferably from 4 to 7 hours.
• terbinafine is recovered from the reaction mixture through a series of steps comprising:
• a pharmaceutically acceptable salt of terbinafine is for example an addition salt with a mineral or organic acid, such as hydrochloric, sulfuric, nitric or malic acid.
• terbinafine can be converted into a pharmaceutically acceptable salt thereof by known methods, e.g. as reported in EP 1236709.
• the process of the invention surprisingly provides terbinafine with enriched stereoisomeric E/Z ratio than the one of the starting compound of formula (II), thus it allows preparation of terbinafine as substantially pure (E)-form even starting from a compound of formula (II) wherein the E/Z ratio is lower than or equal to 95%. Moreover such terbinafine pure (E)-form is endowed with high purity, being in particular free from catalyst residues and other by-products.
• highly pure terbinafine (E)-form is already obtained at this step.
• subsequent isolation of pure terbinafine pure (E)-form can be carried out according to known methods, for example as reported in EP 1236709.
• a further object of the invention is pure terbinafine, namely (E)-N-(6,6-dimethyl -2-hepten-4-ynyl)-N-methyl-1-naphthalenemethanamine, or a pharmaceutically acceptable salt thereof, in particular the hydrochloride, as pure (E)-form and free from catalyst residues, as obtainable by the process of the invention.
• pure is meant having a purity equal to or greater than 99.5%.
• free from catalyst residues is meant a residue amount in platinum catalyst and/or a copper compound lower than 1 p.p.m.
• the process of the invention is particularly suitable for the industrial production of terbinafine, as reaction times are comparatively short and the platinum catalyst can be easily recovered quantitatively, thus remarkably decreasing production costs. Furthermore, the process requires no chromatographic purifications which are known to be time consuming, complex and hardly suitable for the industrial production.
• Tert-butylacetylene and the compound of formula (II) are known products or can be prepared according to known methods, for example as reported in EP 421303.
• a salt of a compound of formula (II) can be obtained by salification of a compound of formula (II) with organic or inorganic acids according to known methods, for example as reported herein.
• a 50 ml 3-necked round-bottom flask equipped with condenser, thermometer and magnetic stirrer, under nitrogen atmosphere, is loaded with 10 g of N-(3-chloro-2-propenyl)-N-methyl-1-naphthalenemethanamine (40.69 mmoles) (E/Z 80/20), 15.8 g of 10% Pt/C with 50% humidity (4.07 mmoles), 1.54 g of CuI (8.14 mmoles), 55.4 g of piperidine (651.1 mmoles) at room temperature.
• the mixture is heated under stirring to approx. 80° C. inner temperature for 30′, then cooled to about 40° C. and 4.68 g of t-butylacetylene (56.96 mmoles) is dropped therein.
• reaction mixture is kept at this temperature for 4 hours, then cooled at room temperature and diluted with 80 ml of toluene and 60 ml of water. Stirring is continued for about 15′, then the mixture is filtered through Celite® and filtration mother liquors are acidified under stirring with 61.9 g of 37% HCl (610.37 mmoles).
• the phases are separated and the toluene phase is evaporated under vacuum at 50° C. to obtain 12.11 g of an oily residue consisting of 11.5 g of terbinafine (95% HPLC purity) corresponding to 97% molar yield.
• a 50 ml 3-necked round-bottom flask equipped with condenser, thermometer and magnetic stirrer, under nitrogen atmosphere, is loaded with 2.05 g of N-(3-chloro-2-propenyl)-N-methyl-1-naphthalenemethanamine oxalate (6.1 mmoles) (E/Z 80/20), 2.38 g of 10% Pt/C with 50% humidity (0.7 mmoles), 0.26 g of CuI (1.4 mmoles), 7.8 g of piperidine (91.5 mmoles) at room temperature. The mixture is heated under stirring to approx. 80° C. inner temperature for 30′, then cooled to about 40° C. and 1.02 g of t-butylacetylene (12.5 mmoles) is dropped therein.
• reaction mixture is kept at this temperature for 4 hours, then cooled at room temperature and diluted with 50 ml of toluene and 25 ml of water. Stirring is continued for about 15′, then the mixture is filtered through Celites® and filtration mother liquors are acidified under stirring with 11.5 g of 37% HCl (116.7 mmoles).
• the phases are separated and the toluene phase is evaporated under vacuum at 50° C. to obtain 1.76 g of an oily residue consisting of 1.70 g of terbinafine (96.5% HPLC purity) (5.86 mmoles) corresponding to 95.6% molar yield.
• a 100 ml 3-necked round-bottom flask equipped with condenser, thermometer and magnetic stirrer, under nitrogen atmosphere, is loaded with 10 g of N-(3-chloro-2-propenyl)-N-methyl-1-naphthalenemethanamine (40.69 mmoles) (E/Z 80/20), 15.8 g of 10% Pt/C with 50% humidity (4.07 mmoles), 1.54 g of CuI (8.14 mmoles), 3.24 g of pyridine (41.0 mmoles) and 40 ml of toluene, at room temperature.
• the mixture is heated under stirring to approx. 80° C. inner temperature for 30′, then cooled to about 40° C. and 4.68 g of t-butylacetylene (56.96 mmoles) is dropped therein.
• reaction mixture is kept at this temperature for 6 hours, then cooled at room temperature and diluted with 40 ml of water. Stirring is continued for about 15′, then the mixture is filtered through Celite® and filtration mother liquors are acidified under stirring with 4.5 g of 37% HCl (0.31 mmoles).
• the phases are separated and the toluene phase is evaporated under vacuum at 50° C. to obtain 11.9 g of an oily residue consisting of 11.3 g of terbinafine (94.9% HPLC purity) corresponding to 95% molar yield.
• a 50 ml 3-necked round-bottom flask equipped with condenser, thermometer and magnetic stirrer, under nitrogen atmosphere, is loaded with 10 g of N-(3-chloro-2-propenyl)-N-methyl-1-naphthalenemethanamine (40.69 mmoles) (E/Z 80/20), 1 g of PtCl 2 (3.76 mmoles), 1.54 g of CuI (8.14 mmoles), 55.4 g of piperidine (650.6 mmoles) at room temperature. The mixture is heated under stirring to approx. 80° C. inner temperature for 30′, then cooled to about 40° C. and 4.68 g of t-butylacetylene (56.96 mmoles) is dropped therein.
• reaction mixture is kept at this temperature for 4 hours, then cooled at r.t. and diluted with 40 ml of toluene and 80 ml of water. Stirring is continued for about 15′, then the mixture is filtered through Celite® and filtration mother liquors are acidified under stirring with 56 g of 37% HCl (570 mmoles).
• the phases are separated and the toluene phase is evaporated under vacuum at 50° C. to obtain 13.0 g of an oily residue consisting of 11.5 g of terbinafine (88% HPLC purity) (39.4 mmoles) corresponding to 96.9% molar yield.
• a 500 ml 4-necked round-bottom flask equipped with thermometer and magnetic stirrer, under nitrogen atmosphere, is loaded with 80 g of N-(3-chloro-2-propenyl)-N-methyl-1-naphthalenemethanamine (325 mmoles) (E/Z 80/20) and 317 g of methanol at room temperature.
• the resulting solution is added with 29.3 g of oxalic acid (325 mmoles), keeping stirring for 15′, then the precipitate is filtered and the product is washed with methanol on the filter.
• a 50 ml 3-necked round-bottom flask equipped with condenser, thermometer and magnetic stirrer, under nitrogen atmosphere, is loaded with 3 g of N-(3-chloro-2-propenyl)-N-methyl-1-naphthalenemethanamine (12.0 mmoles) (E/Z 98/2), 0.27 g of Pt/C 10% (about 50% humidity) (0.069 mmoles), 0.027 g of CuI (0.14 mmoles), 3.11 g of piperidine (36 mmoles) at room temperature. The mixture is heated under stirring to approx. 80° C. inner temperature for 30′, then cooled to about 40° C. and 1.29 g of t-butylacetylene (16 mmoles) is dropped therein.
• the reaction mixture is heated at 80° C. and is kept in these conditions for 3 hours, then is cooled at r.t. and diluted with 40 ml of toluene and 80 ml of water. Stirring is continued for about 15′, then the mixture is filtered through Celite® and filtration mother liquors are acidified under stirring with 3.1 g of 37% HCl (31.6 mmoles).
• the phases are separated and the toluene phase is evaporated under vacuum at 50° C. to obtain 3.60 g of an oily residue consisting of 3.42 g of terbinafine (99.5% HPLC purity) (11.76 mmoles) corresponding to 98% molar yield.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Health & Medical Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Communicable Diseases (AREA)
• Oncology (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Chemical & Material Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Applications Claiming Priority (3)

Publications (2)

Family

ID=32448913

Family Applications (1)

Country Status (10)

Cited By (3)

Citations (4)

• 2002
  • 2002-11-29 IT IT002534A patent/ITMI20022534A1/it unknown
• 2003
  • 2003-11-21 WO PCT/EP2003/013124 patent/WO2004050604A2/en not_active Ceased
  • 2003-11-21 US US10/536,312 patent/US7288678B2/en not_active Expired - Fee Related
  • 2003-11-21 EP EP03808278A patent/EP1575899A2/de not_active Withdrawn
  • 2003-11-21 HR HR20050414A patent/HRP20050414A2/xx not_active Application Discontinuation
  • 2003-11-21 JP JP2004556166A patent/JP2006508156A/ja active Pending
  • 2003-11-21 AU AU2003302616A patent/AU2003302616A1/en not_active Abandoned
  • 2003-11-21 CA CA002507587A patent/CA2507587A1/en not_active Abandoned
  • 2003-11-21 KR KR1020057009508A patent/KR20050086867A/ko not_active Withdrawn
  • 2003-11-21 PL PL377169A patent/PL377169A1/pl unknown

Patent Citations (5)

Non-Patent Citations (3)

Also Published As

Similar Documents

Legal Events